IDH1 and IDH2 mutations as novel therapeutic targets: Current perspectives

Johanna Mondesir, Christophe Willekens, Mehdi Touat, Stéphane de Botton

    Résultats de recherche: Contribution à un journalArticle 'review'Revue par des pairs

    174 Citations (Scopus)

    Résumé

    Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that convert isocitrate to α-ketoglutarate. IDH1/2 mutations define distinct subsets of cancers, including low-grade gliomas and secondary glioblastomas, chondrosarcomas, intrahepatic cholangiocarcinomas, and hematologic malignancies. Somatic point mutations in IDH1/2 confer a gain-of-function in cancer cells, resulting in the accumulation and secretion in vast excess of an oncometabolite, the D-2-hydroxyglutarate (D-2HG). Overproduction of D-2HG interferes with cellular metabolism and epigenetic regulation, contributing to oncogenesis. Indeed, high levels of D-2HG inhibit α-ketoglutarate-dependent dioxygenases, including histone and DNA demethylases, leading to histone and DNA hypermethylation and finally a block in cell differentiation. Furthermore, D-2HG is a biomarker suitable for the detection of IDH1/2 mutations at diagnosis and predictive of the clinical response. Finally, mutant-IDH1/2 enzymes inhibitors have entered clinical trials for patients with IDH1/2 mutations and represent a novel drug class for targeted therapy.

    langue originaleAnglais
    Pages (de - à)171-180
    Nombre de pages10
    journalJournal of Blood Medicine
    Volume7
    Les DOIs
    étatPublié - 1 janv. 2016

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